The NMDA antagonist, dizocilpine, enhances cocaine reinforcement without influencing mesoaccumbens dopamine transmission.

In order to assess the role of excitatory amino acids (EAAs) in the reinforcing property of cocaine, the NMDA antagonist, dizocilpine, or the AMPA antagonist, DNQX, were administered to animals previously trained to self-administer cocaine (1.0, 0.4 or 0.16 mg/kg per infusion). The highest doses of dizocilpine (0.1 mg/kg, IP) and DNQX (30 mg/kg, IP) significantly reduced operant responding for cocaine maintained on a fixed ratio schedule of reinforcement. However, whereas dizocilpine had no influence operant responding for food, DNQX significantly decreased lever pressing for this reinforcer. These results indicate that an NMDA antagonist produces a relatively selective enhancement of cocaine reinforcement, while an AMPA antagonist decreases cocaine self-administration only at a dose that also impairs responding for an alternate reinforcer. A parallel in vivo microdialysis study performed in freely moving rats tested the effects of dizocilpine alone and in combination with cocaine on extracellular dopamine in the nucleus accumbens shell. The results revealed that dizocilpine alone (0.1 mg/kg, IP) did not alter basal extracellular dopamine levels in the nucleus accumbens or spontaneous behavior. In addition, 0.1 mg/kg dizocilpine did not alter the increase in dopamine in the accumbens shell or behavioral hyperactivity produced by cocaine (15 or 30 mg/kg). Collectively, these findings suggest that dizocilpine enhances the reinforcing effect of cocaine without influencing dopamine transmission in the nucleus accumbens shell.